Novelty exploration-activated ensemble in the lateral hypothalamus confers analgesic and anxiolytic effects

While attention distraction alleviates pain and negative affect, the underlying neural circuits remain unclear. Here, we show that novelty exposure, a means to attract attention, significantly alleviates acute and chronic pain in mice. Using a Fos-driven viral strategy, we identified a lateral hypothalamus (LH) neuronal ensemble activated during novelty exploration. This novelty ensemble also responds to pain- and anxiety-like stimuli. Activation of this ensemble produces analgesic and anxiolytic effects, whereas its inhibition exacerbates pain and anxiety-like behavior in mouse pain models. The LH ensemble comprises both GABAergic and glutamatergic subpopulations, both contributing to pain and anxiety modulation. However, activating their specific projections to the lateral preoptic area, lateral habenula, ventral tegmental area, and lateral periaqueductal gray regulates pain and anxiety in distinct patterns. Together, we define an LH novelty-activated neuronal subpopulation mediating the analgesic and anxiolytic benefits of novelty exposure, revealing circuit-specific targets for relieving pain and anxiety. This study shows that novelty exposure alleviates pain and anxiety in mice by activating a specific ensemble of neurons in the lateral hypothalamus, revealing distinct neural circuits that mediate the therapeutic benefits of attention distraction.